Luminal degradation

Ribosomes remain attached to the ER during synthesis of signal peptide-containing proteins but are released and dissociated into their two types of subunits when the process is completed. The signal peptide is hydrolyzed by signal peptidase, located on the luminal side of the ER membrane (Figure 46-4), and then is apparently rapidly degraded by proteases. 

Much of the pulmonary NEP activity is believed to reside in the epithelium, as has been demonstrated in the ferret (Borson et al., 1986), and thus it is likely that inhaled ozone would preferentially destroy luminal NEP before affecting any enzymes in the vasculature, which may degrade peptides delivered by the intravenous route. This may explain the route-dependency of BHR after ozone in guinea pigs. Further evidence that the oxidant effects of inhaled ozone are selective is provided by the findings that pressor responses to angiotensin I (which requires conversion by ACE to angiotensin II) were not altered by ozone exposure (Yeadon et eU., 1992). 

The degradation and formation of nonabsorbable drug complexes in the intestinal lumen is the third factor, in addition to dissolution and permeability, which could affect fraction absorption. Limitations of bioavailability due to these factors seem to be less frequent compared with the two other main factors. Regulatory guidelines for BCS-based biowaivers still ask for in vitro studies of luminal degradation in relevant test media, whereas specific binding studies are not required [17]. 

The bacteria in the intestinal tract serve as another well-known source of luminal drug degradation [61], though this is only important for the colon region as the luminal concentration of bacteria is 104 to 109-fold higher in the colon compared with the small intestine. Thus, this aspect is only relevant for drugs that reach this region, for example, due to poor permeability, slow dissolution or delivery by modified-release formulations. Hydrolytic and other reductive reactions are predominantly mediated by bacterial enzymes, and a list of the most prominent types... 

In situ models are to evaluate absorption or membrane permeability under the physiologically relevant tissue condition. While the luminal environment can be modulated by the administered solution, the tissue condition is physiologically controlled. The estimated membrane permeability can be, in most cases, assumed to represent the transport across the epithelial cell layer at steady state or quasisteady state. However, one needs to be aware that the involvement of metabolic degradation, which may occur at the cellular surface or within the cytosol, can be a factor leading to biased estimates of membrane permeability and erroneous interpretation of the transport process. Particularly,... 

Intestinal Metabolism Intestinal drug metabolism can occur by microflora present in the gut lumen, as well as by enzymes present in luminal fluids and in the intestinal mucosa [166], Metabolism of xenobiotics by gut microflora is low in comparison to metabolism by the gut mucosa and liver [62], However, the intestinal microflora (e.g., Bacteroides and Bifidobacteria) may play an important role in the first-pass metabolism of compounds that are poorly or incompletely absorbed by the gut mucosa, especially in the lower parts of the intestine. This bacterial metabolism is largely degradative,... 

Hiller, M. M., Finger, A., ScHWEiGER, M., and Wole, D. H. ER degradation of a misfolded luminal protein by the cytosolic ubiuqitin-proteasome pathway. Science 1996,... 

Initial current, voltage, luminance, color coordinate properties, and luminance degradation properties were evaluated for the step 5 product and a styryl comparative. Testing results are provided in Table 1. 

Bemkop-Schntirch, A. and Gockel, N.C. (1997). Development and analysis of a polymer protecting from luminal enzymatic degradation of a—chymotrypsin. Drug Dev. Ind. Pharm., 23, 733-740. 

These lipids are then packaged into spherical lipoproteins, particles of lipids and proteins, known as chylomicrons, which are secreted into lymphatic vessels and subsequently enter the blood stream. Once in the circulatory system the triacylglycerol components of the chylomicrons are degraded to fatty acids and glycerol by the enzyme lipoprotein lipase, which is attached to the luminal (inner) side of capillary vessels in heart, muscle, adipose (commonly... 

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